Oxidative stress accompanies both normal and pathological processes. Because we live in an oxygen rich environment, we need protective mechanisms to deal with inevitable release of highly reactive oxygen free radicals resulting from both normal and pathological events such as stroke. Our primary defense against oxidative radicals consists of a series of enzymes and proteins. However, the products of these detoxification steps can yield another radical, e.g. hydroxyl, or an unstable molecule, hydrogen peroxide requiring another step of detoxification. Normally, there are sufficient levels of protective enzymes to cope with these products. However, under pathological circumstances, these intermediate steps are overwhelmed; radicals and their deleterious products accumulate. Antioxidant therapies that modify only one radical in this cascade may generate unstable intermediates that, in the face of inadequate downstream protective mechanisms, can lead to the accumulation of more radicals. It is not therefore surprising that clinical trials of conventinal antioxidant therapies have generally failed. Our laboratories have developed a new, innovative class of antioxidant using highly modified carbon nanoparticles termed PEGylated hydrophilic carbon clusters (PEG-HCCs). These particles have a high radical quenching capacity and generate oxygen during superoxide quenching, potentially ideal to treat ischemia/reperfusion. Furthermore, PEG-HCCs can be targeted using antibodies, peptides and small molecules. Importantly, they were effective after oxidative stress in cell culture while conventional antioxidants required pre-treatment. Based on our finding that PEG-HCCs rapidly restored cerebral blood flow in a model of traumatic brain injury, we hypothesize that we can develop an effective formulation in stroke. Preliminary results in a severe test in hyperglycemic transient middle cerebral artery occlusion (tMCAO) in the rat suggested improved survival. In Aim 1, we will test the ability to extend the therapeutic window using PEG-HCCs in a model of normo- and hyper-glycemic tMCAO. In Aim 2, we will test modifications intended to augment their targeting and distribution to the brain. We selected hyperglycemic stroke since it is a common co-morbidity in stroke causing increased mortality and poorer outcomes, particularly afer recanalization therapies such as clot removal. While oxidative stress is important in normoglycemic stroke, the mechanisms are quantitatively much greater in extended periods of ischemia and in hyperglycemia. Should these be successful, we will pursue the additional pre-clinical studies necessary for an IND application for human testing in stroke as a potential treatment for those who otherwise would have the worst outcomes.